p53 and pRb prevent rereplication in response to microtubule inhibitors by mediating a reversible G1 arrest.
Cell cycle checkpoints are safeguards that ensure the initiation of downstream events only after completion of upstream processes. The tumor suppressors p53 and pRb prevent initiation of a second round of replication in response to spindle inhibitors, but it has yet to be proven that this is a mitotic checkpoint response. We show that asynchronous human fibroblasts arrest in G1 with 4 N DNA content after nocodazole treatment, whereas isogenic p53- and pRb-deficient fibroblasts rereplicate. Importantly, nocodazole elicits a reversible arrest in G0-G1 synchronized normal human fibroblasts but not in isogenic p53-deficient derivatives. Furthermore, the G1 cyclin-dependent kinase inhibitors p21 and p16 also play critical roles in limiting rereplication. Hence, p53 and pRb are required during G1 to prevent entry into a replicative cycle and appear to provide a connection between the structural integrity of the microtubules and the cell cycle machinery in interphase cells.
Khan
S H
SH
Department of Biology, University of California at San Diego, La Jolla 92037, USA.
Wahl
G M
GM
D000782:Aneuploidy; D000970:Antineoplastic Agents / Q000494:pharmacology; D002453:Cell Cycle; D002478:Cells, Cultured; D019941:Cyclin-Dependent Kinase Inhibitor p16 / Q000502:physiology; D050759:Cyclin-Dependent Kinase Inhibitor p21; D016213:Cyclins / Q000502:physiology; D004261:DNA Replication / Q000187:drug effects*; D005347:Fibroblasts / Q000187:drug effects; D016193:G1 Phase / Q000187:drug effects*; D006801:Humans; D008870:Microtubules / Q000187:drug effects*; D015739:Nocodazole / Q000494:pharmacology*; D010766:Phosphorylation; D011499:Protein Processing, Post-Translational; D016160:Retinoblastoma Protein / Q000172:deficiency / Q000494:pharmacology / Q000502:physiology*; D016159:Tumor Suppressor Protein p53 / Q000172:deficiency / Q000494:pharmacology / Q000502:physiology*
D000970:Antineoplastic Agents; C493956:CDKN1A protein, human; D019941:Cyclin-Dependent Kinase Inhibitor p16; D050759:Cyclin-Dependent Kinase Inhibitor p21; D016213:Cyclins; D016160:Retinoblastoma Protein; D016159:Tumor Suppressor Protein p53; D015739:Nocodazole